Summary Small-animal positron emission tomography (PET) has been widely used as a powerful tool for preclinical studies to image a wide range of biological processes in vivo. The key parameters in PET are its spatial resolution and sensitivity that determine the ability to image and quantify radiotracers in a small region of the subject at sub- nanomolar concentrations. However, the applications of small-animal PET have been limited in its application by a combination of spatial resolution and more importantly, the sensitivity, which hampers the use of PET for a range of applications including imaging of low-levels of receptor and transgene expression, imaging of therapeutic cell circulation and fast dynamic imaging to capture cardiac dynamics. The main goal of this proposal is to develop a very high sensitivity total-body small-animal PET scanner dedicated for ultra-low dose and fast dynamic applications for imaging mouse/rat disease models. The proposed PET scanner will have 72 depth-of-interaction (DOI) detector modules arranged in 6 rings, with a ring diameter of 160 mm and an axial length of 242 mm. The geometry of the proposed PET scanner is designed to cover the whole body of the mouse/rat and to obtain high sensitivity and high resolution across the entire body. Dual-ended readout detectors based on SiPMs coupled to both ends of bismuth germanate (BGO) will be used to extract DOI information to maintain high and uniform spatial resolution across the whole field of view (FOV). BGO is chosen due to its high stopping power, high photoelectric ratio, low cost and the most importantly its negligible background radiation (which can significantly reduce the background events to benefit ultra-low dose imaging). While lutetium-based scintillators have many attractive properties, a major limitation is the presence of intrinsic background radiation, which is a significant barrier for ultra-low dose imaging. Dedicated data acquisition electronics will be designed for the proposed scanner. Specifically, a novel analog signal multiplexing readout method using Schottky diodes to block the noise of SiPMs with negligible signals will be used to simplify the readout electronics and to improve the spatial resolution and the timing resolution, and a shared-photodetector readout method will be used to identify all the crystals. The outcome of this proposal will be a PET scanner will have a sensitivity >50% at the center of the FOV and a sensitivity > 40% within the central 100 mm of the axial FOV. The resolution is predicted to be ~ 1 mm at the center of the FOV and better than 1.5 mm across the entire FOV. The sensitivity is more than 4x better than currently available small-animal PET scanners. It can potentially promote the use of total-body small-animal PET for monitoring biological processes that result in very low source activities and expand the range of applications for this powerful, non-invasive and translational imaging modality in preclinical applications. The PET scanner developed in this proposal is also MRI-compatible and will support eventual integration inside an MRI scanner for hybrid PET/MRI imaging.